Link between nerve and blood vessel development called into question

In a number of tissues, the growth of nerves and blood vessels appears to be …

Sometimes, the cleanest experiments are not the ones that support the consensus that the scientific community likes but rather the ones that put a knife in its back. As T.H. Huxley noted, even the most beautiful hypothesis can be slain by a single ugly fact. For a model that explained the apparent coordination between the development of nerves and blood vessels, that fact appears to have arrived, thanks to some nicely done genetic experiments that appear in this month's issue of Development.

The model in question explains an old observation: in many tissues, especially the limbs, the branching of nerves and the branching of blood vessels appear suspiciously similar, as if the two processes shared a common regulatory system. An apparent regulatory link came in the form of proteins called neuropilins. These proteins were first identified on nerve cells, where they were found to act as receptors for a nerve guidance signal, semaphorin 3. The surprise came when other researchers found that neuropilins also show up on the cells of blood vessels, and that they can also bind the blood vessel guidance protein VEGF.

The obvious inference was that the combination of semaphorins and VEGF could compete for the attention of neuropilins on both nerves and blood vessels, allowing a single pathway to provide guidance cues to both types of tissue. Scientists loved this proposal, as it combined phenomenon and mechanism in a tidy package. Experiments done in cultured cells also seemed to support it. The only place where data was lacking was in actual animals.

That last, key bit of experimental support may never be had. The new paper describes what happened when researchers looked at blood vessel development in mice engineered to lack Semaphorin 3a. The answer was nothing—blood vessel development appeared normal, and was far better than when the mice lacked a specific form of VEGF. Conversely, nerves were indifferent to the dose of VEGF, but showed defects when Semaphorin 3a was eliminated. The authors tried various combinations of mutations in the two genes to look for some sort of genetic interaction, but all blood vessels cared about was whether VEGF was around.

So, researchers are going to have to keep looking for the connection between blood vessels and nerves (the authors note some promising results with a receptor called plexin D1). But the data make for a good reminder that, given a limited set of data—and scientific data is always limited in one way or another—the obvious model may not always be the right one.